Nephrolithiasis (NL) affects up to 10% of the population, and symptomatic kidney stone episodes produce significant pain, suffering and economic costs (up to $5.3 billion per year in the United States). Nevertheless, treatment strategies are imperfect and relatively unchanged over the last 30 years, in part since this common disease process remains understudied. Further, although generally considered a benign albeit painful condition, recent evidence suggests NL may predispose to chronic kidney disease (CKD) or even end stage renal disease (ESRD), as our preliminary review of Olmsted County, MN data also supports. Given its substantial prevalence, NL could potentially contribute a sizable number of patients with renal failure. Therefore, this R21 grant will attempt to fill a critical gap in our knowledge base by examining the true nature of the association of NL and CKD. Resources of the Rochester Epidemiology Project will be used to assemble and analyze a community-based cohort of Olmsted County NL patients diagnosed since 1980. This cohort will be characterized via a complimentary combination of record review and mail-out survey to establish important epidemiological associations of NL with CKD, ESRD, and hypertension (HTN). From this entire cohort (n = 3680), 50 NL subjects and 50 matched controls will be recruited for intensive study. Specific Aims are: Aim #1: Clarify disease associations with renal stones in the population-based Olmsted County NL cohort compared to matched controls using: a) a systematic electronic medical record screen of all ICD diagnoses and a mail-out patient survey; b) analysis of electronic lab data to determine if CKD is more common amongst the Olmsted County NL cohort compared to a matched control cohort; c) a nested-case control design to identify risk factors for ESRD amongst the Olmsted County NL cohort; d) a retrospective cohort design to identify risk factors for HTN amongst the Olmsted County NL cohort, in order to elucidate the nature of the association between NL and HTN Aim #2: Compare urinary lithogenic risk factors and CKD risk factors between 50 NL patients and 50 matched controls, in order to determine key factors that differentiate the two groups The primary goal of this proposal is to clarify the nature of the association between CKD and NL, in order to determine if NL contributes significantly to the CKD/ESRD population. Preliminary data from this proposal will also be used to support future grants to define genetic associations with urinary lithogenic factors and NL risk in order to improve understanding regarding the pathogenesis of NL, and hence identify new therapeutic targets. This will gain additional urgency if in fact we demonstrate that NL is a significant risk factor for CKD. [unreadable] [unreadable] [unreadable]